This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV infection in humans is initiated by lymphocyte-tropic CCR5-dependent transmitted/founder viruses with reduced capacity for macrophage infection, indicating that in infected hosts macrophage-tropic variants evolve de novo. Whether the evolution of M-tropism is purely stochastic or there are selective forces at play that suppress or promote the emergence of these quasispecies, is not clear. To ascertain the role of host factors in the evolution of macrophage tropism, we analyzed the reciprocal relationships between the development of M-tropic variants, anti-viral humoral responses, and availability of target lymphocytes in longitudinal samples collected from SIVmac239-infected rhesus macaques. Circulating T- and M-tropic quasispecies were quantified with a SNP-genotyping assay, neutralizing responses were assessed by inhibition of cell-to-cell fusion, and the changes in lymphocyte populations were monitored by flow cytometry. The development of M-tropism was detected in 63% of the animals in the cohort. The emergence of M-tropic species was associated with lower neutralizing responses and was independent of CD4+CCR5+ lymphocyte population. Yet, the loss of target lymphocytes in the terminal phase of infection was associated with rapid growth of the established M-tropic population. Our data suggest a dual host effect on the evolution of peripheral M-tropic species: plasma neutralizing responses tend to regulate the emergence of circulating M-tropic variants, with lower responses providing the permissive conditions for virus adaptation to macrophages. Once a M-tropic population emerges, the loss of the target CD4+CCR5+ T lymphocytes may act as a 'conditional'force driving the expansion of the M-tropic population.